The hallmark of HIV-1 infection is an early and chronic inversion of the CD4+:CD8+ ratio due to a reduction of CD4+ numbers. The investigators have demonstrated that cats naturally or experimentally infected with Feline Immunodeficiency Virus (FIV) also show an inverted CD4+:CD8+ ratio due to decreased numbers of CD4+ cells. They hypothesize that, similar to HIV-1, the immunopathogenesis of FIV infection can be attributed to infection and loss of CD4+ lymphocytes. The overall objective of the proposal is to study the cellular and molecular characteristics of virus/cell interactions during the acute and early asymptomatic or chronic stages of FIV infection, including phenotypic and functional changes in the immune system. Secondly, they will study the role of secondary viral infections as co-factors in precipitating clinical AIDS in FIV-infected asymptomatic cats. Random source and SPF cats will be inoculated with FIV, and lymphocyte numbers and CD4+:CD8+ ratios measured at weekly intervals for 24 weeks. In vivo targets of FIV infection will be determined on FACS or Ab-coated Dynal beads enriched monocytes and CD4+ and CD8+ lymphocytes. FIV expression will be quantitated by reverse transcriptase (RT) and polymerase chain reaction (PCR) using primers and probes for sequences in the gag gene and by in situ hybridization for FIV mRNA. Frequency of infection will also be determined on purified cell types by limiting dilution RT and PCR analyses. Immunological and virological characteristics of the asymptomatic stage of the infection will be further investigated by FIV gene transcription activation studies with molecules such as TNF- , PMA and LPS. Other experiments are designed to evaluate the possible role of FIV-specific CD8+ (Tc/s) cells in regulating FIV gene expression and CD4+ numbers and function. Effects of FIV infection on immune function with disease progression will be measured by response to mitogens and specific antigens, IL-1 and IL-2 production and lymphocyte cytotoxic (NK, LAK, CTL, ADCC) functions. Finally, they will study the effect of secondary exposure of FIV-infected, asymptomatic cats to replicating and non-replicating Feline Herpesvirus (FHV) and Feline Leukemia Virus (FeLV). Clinical, immunological and virological parameters will be followed to determine if secondary viral infections or antigenic stimulation function as co-factors in the pathogenesis of FIV-induced AIDS.